Discovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors

We report the discovery and synthesis of a novel series of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors. A representative dihydrothieno compound was advanced into a PC3-NCI prostate mouse tumor model in which it demonstrated a dose-dependent reduction in tumor growth and st...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2010-12, Vol.20 (23), p.7037-7041
Main Authors: Bencsik, Josef R., Xiao, Dengming, Blake, James F., Kallan, Nicholas C., Mitchell, Ian S., Spencer, Keith L., Xu, Rui, Gloor, Susan L., Martinson, Matthew, Risom, Tyler, Woessner, Richard D., Dizon, Faith, Wu, Wen-I, Vigers, Guy P.A., Brandhuber, Barbara J., Skelton, Nicholas J., Prior, Wei Wei, Murray, Lesley J.
Format: Article
Language:English
Subjects:
Akt
AKT protein
Animals
Antineoplastic agents
Binding Sites
Biological and medical sciences
Disease Models, Animal
Dose-Response Relationship, Drug
General aspects
Kinase
Male
Medical sciences
Mice
Oral
Pharmacology. Drug treatments
PKA
Prostatic Neoplasms - drug therapy
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Proto-Oncogene Proteins c-akt - antagonists & inhibitors
Pyrimidines - chemistry
Pyrimidines - pharmacology
Selectivity
Structure-Activity Relationship
Tumor Burden - drug effects
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Summary:We report the discovery and synthesis of a novel series of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors. A representative dihydrothieno compound was advanced into a PC3-NCI prostate mouse tumor model in which it demonstrated a dose-dependent reduction in tumor growth and stasis when dosed orally daily at 200 mg/kg. Herein we report the discovery and synthesis of a novel series of dihydrothieno- and dihydrofuropyrimidines ( 2 and 3) as potent pan Akt inhibitors. Utilizing previous SAR and analysis of the amino acid sequences in the binding site we have designed inhibitors displaying increased PKA and general kinase selectivity with improved tolerability compared to the progenitor pyrrolopyrimidine ( 1). A representative dihydrothieno compound ( 34) was advanced into a PC3-NCI prostate mouse tumor model in which it demonstrated a dose-dependent reduction in tumor growth and stasis when dosed orally daily at 200 mg/kg.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2010.09.112